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Acute lymphoblastic leukemia

Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia

Leukemia volume 29, pages 2317–2327 (2015)Cite this article

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Abstract

The TLX1 transcription factor is critically involved in the multi-step pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanism by which these T-cell specific oncogenes cooperate during transformation remains to be established. Here, we used chromatin immunoprecipitation followed by sequencing to establish the genome-wide binding pattern of TLX1 in human T-ALL. This integrative genomics approach showed that ectopic TLX1 expression drives repression of T cell-specific enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 at critical target genes, including IL7R and NOTCH3. These phenomena coordinately trigger a TLX1-driven pre-leukemic phenotype in human thymic precursor cells, reminiscent of the thymus regression observed in murine TLX1 tumor models, and create a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multi-step pathogenesis of TLX1-driven human leukemia.

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Acknowledgements

We would like to thank following funding agencies: the Fund for Scientific Research Flanders (‘FWO Vlaanderen’ research projects G.0202.09, G.0869.10N, 3G055013N, 3G056413N to FS; 3GA00113N, 3G065614, G.0C47.13N to PVV and G0B2913N, G037514N, 3G002711 to TT; doctoral grant to AW, postdoctoral grants to IvdW, TT, PVV and PR; BP is a senior clinical investigator), IWT Vlaanderen (PhD grant to KD); Ghent University (GOA grant 01G01910 to FS), the Cancer Plan from the Federal Public Service of Health (FS), the Children Cancer Fund Ghent (FS) and the Belgian Program of Interuniversity Poles of Attraction (IUAP P7/03 and P7/07). Additional funding was provided by the Cancéropole IDF, the CIT program from the Ligue Contre le Cancer, ERC St Grant Consolidator 311660, and the ANR-10-IBHU-0002 Saint-Louis Institute program (JS). We also would like to thank Aline Eggermont for excellent technical assistance.

Author contributions

KD performed and analyzed experiments and wrote the paper. WVL and MO performed bioinformatics on large-scale data sets. JVdM, IVdW, PR, AW and CEdB performed experiments. JC, JS, BP, NVR, TT, FS and PVV designed the experiments, directed research, analyzed data and wrote the paper. All the authors read and edited the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics and Genetics, Center for Medical Genetics, Ghent University, Ghent, Belgium

    K Durinck, W Van Loocke, J Van der Meulen, M Ongenaert, P Rondou, A Wallaert, N Van Roy, B Poppe, F Speleman & P Van Vlierberghe

  2. Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium

    I Van de Walle & T Taghon

  3. Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, KU Leuven and Center for the Biology of Disease, VIB, Leuven, Belgium

    C E de Bock & J Cools

  4. Genome Rearrangements and Cancer Laboratory, U944 INSERM, University Paris Diderot and Hematology Laboratory, Saint-Louis Hospital, Paris, France

    J Soulier

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  1. K Durinck
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Correspondence to P Van Vlierberghe.

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Durinck, K., Van Loocke, W., Van der Meulen, J. et al. Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia. Leukemia 29, 2317–2327 (2015). https://doi.org/10.1038/leu.2015.162

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